The "Old" and the "New" Antibiotics for MDR Gram-Negative Pathogens: For Whom, When, and How

Abstract

The recent expansion of multidrug resistant and pan-drug-resistant pathogens poses significant challenges in the treatment of healthcare associated infections. An important advancement, is a handful of recently launched new antibiotics targeting some of the current most problematic Gram-negative pathogens, namely carbapenem-producing Enterobacteriaceae (CRE) and carbapenem-resistant P. aeruginosa (CRPA). Less options are available against carbapenem-resistant Acinetobacter baumannii (CRAB) and strains producing metallo-beta lactamases (MBL). Ceftazidime-avibactam signaled a turning point in the treatment of KPC and partly OXA- type carbapenemases, whereas meropenem-vaborbactam was added as a potent combination against KPC-producers. Ceftolozane-tazobactam could be seen as an ideal beta-lactam backbone for the treatment of CRPA. Plazomicin, an aminoglycoside with better pharmacokinetics and less toxicity compared to other class members, will cover important proportions of multi-drug resistant pathogens. Eravacycline holds promise in the treatment of infections by CRAB, with a broad spectrum of activity similar to tigecycline, and improved pharmacokinetics. Novel drugs and combinations are not to be considered "panacea" for the ongoing crisis in the therapy of XDR Gram-negative bacteria and colistin will continue to be considered as a fundamental companion drug for the treatment of carbapenem-resistant Enterobacteriaceae (particularly in areas where MBL predominate), for the treatment of CRPA (in many cases being the only in vitro active drug) as well as CRAB. Aminoglycosides are still important companion antibiotics. Finally, fosfomycin as part of combination treatment for CRE infections and P. aeruginosa, deserves a greater attention. Optimal conditions for monotherapy and the "when and how" of combination treatments integrating the novel agents will be discussed.

Keywords: Acinetobacter baumannii; Pseudomonas aeruginosa; carbapenemase producing Klebsiella pneumoniae; ceftazidime avibactam; ceftolozane tazobactam; colistin; combination; monotherapy.

Figure 1

Prerequisite conditions for selecting monotherapy as definitive treatment of infections by extensively-drug-resistant (XDR) pathogens. PK/PD, pharmacokinetic/pharmacodynamic; MDR, multi-drug -resistant; MIC, minimum inhibitory concentration; XDR, extensively-drug-resistant.

Figure 2

How to optimize treatment of Carbapenem-Resistant Enterobacteriaceae (CRE). CAZ-AVI, ceftazidime avibactam; CRE, carbapenem-resistant Enterobacteriaceae; MER/VAB, meropenem vaborbactam; MIC, minimum inhibitory concentration. ≠ OXA-48 is permissive only for CAZ-AVI. ^*Components of the combination will be based on: (i) epidemiology data (for empirical regimen); (ii) pharmacokinetic/pharmacodynamic considerations relating to the source of infection; (iii) lower MIC (if possible, avoidance of antibiotics with borderline susceptibility). ∧ Selection of CAZ-AVI or MER/VAB in definitive treatment precludes demonstrated in vitro susceptibility and absence of detected metallo-beta lactamase mechanism of resistance; for MER/VAB absence of OXA as well. ^Δ Higher MICs against meropenem (up to 64 mg/L) may require higher doses and therapeutic drug monitoring.

Figure 3

How to optimize treatment of Multi-drug-resistant Pseudomonas aeruginosa. CAZ-AVI, ceftazidime avibactam; CLZ/TAZ, ceftolozane tazobactam; MDR, Multi-drug resistant; MIC, minimum inhibitory concentration; XDR, extensively drug-resistant; VAP, ventilator-associated pneumonia. ^*Components of the combination will be based on: (i) epidemiology data (for empirical regimen); (ii) pharmacokinetic/pharmacodynamic considerations relating to the source of infection; (iii) lower MIC (if possible, avoidance of antibiotics with borderline susceptibility). ∧ Selection of CAZ-AVI in definitive treatment precludes demonstrated in vitro susceptibility and absence of detected metallo-beta lactamase mechanism of resistance.